Structural transitions of DNA and docking of DNA-binding ligands on DNA are fundamental processes in molecular biology. Understanding and controlling these processes are essential to the rational design of novel drugs against cancer and infectious diseases such as HIV. Single-molecule force measurements using optical and magnetic tweezers and atomic force microscopy have dramatically expanded our knowledge of nucleic acids and proteins. Specifically, stretching single DNA molecules by an optical tweezers instrument can induce the unwinding of the two strands of the DNA duplex. The induced structural and thermodynamic changes in the DNA double helix upon stretching alter interactions with DNA-binding ligands in a controllable and measurable way. Therefore single-molecule force measurements of DNA and DNA-ligand interactions provide an unprecedented opportunity for quantitative study of a wide range of physiologically important phenomena associated with DNA helix-destabilization and DNA-ligand binding. In spite of the progress made in single-molecule force experiments, a poor understanding of the structural and thermodynamic response of biomolecules to mechanical stress has limited the insight that such experiments have provided into helix destabilization and DNA-ligand binding. A notorious difficulty for modeling force-induced melting is the vast range of length and time scales spanned by the process, and by the difficulty in computing the accompanying change in entropy. To better understand the fundamental biophysics involved in crossing length and times scales from the atomistic to the macromolecular model, we develop a novel multiscale model for DNA stretching and small ligand binding to stretched DNA. This system is well characterized experimentally and sufficiently simple to facilitate chemically accurate biophysical modeling in terms of all-atom molecular dynamics (MD) simulations and coarse-grained models such as the Poland-Scheraga model. Moreover, DNA stretching in the presence of DNA binding ligands yields information about DNA ligand binding under realistic, biologically relevant conditions that cannot be obtained by other methods. In this project we study the binding of Actinomycin D (ActD), an anticancer antibiotic drug that targets DNA replication and transcription, by a multipronged approach. On the atomistic scale, chemically accurate MD simulations will be used to study the binding mechanism and dynamics of ActD to short DNA oligomers; for long DNA as used in stretching experiments, our multiscale model will be used to compute equilibrium force-extension relations that can be directly validated with experimental data. The project will both enhance our knowledge of multiscale phenomena in fundamental biophysics and provide new insight into the anticancer function of ActD.